The Impact of Antiepileptic Drugs on Thyroid Function in Children with Epilepsy: New Versus Old.

Objectives To investigate the effects of traditional antiepileptic drugs (AEDs) versus newer AEDs on the thyroid hormone profile of children with epilepsy. Materials & Methods A total of 80 children with epilepsy were included in this study and were divided into two groups. Group 1 included 40 children with epilepsy on traditional AEDs, and group 2 included 40 children with epilepsy on newer AEDs. Forty healthy children were also included as the control group (group 3). We analyzed the serum levels of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH). Results: In epileptic children treated with traditional drugs, there was a significant reduction in the serum level of FT4 and a significant increase in TSH concentration, compared to the control group (P<0.001). Conversely, epileptic children treated with newer AEDs showed no significant changes in the serum concentrations of FT3, FT4, and TSH, compared to the control group. Conclusion: Traditional AEDs have more significant effects on thyroid hormone profile, compared to newer AEDs.


Introduction
Epilepsy is a common neurological disorder, characterized by a disturbance in the electrical activity of the brain due to different factors. It includes many types of seizures with variable severity, seizure semiology, etiology, consequences, and management (1). It is a chronic disorder, which requires long-term therapy with antiepileptic drugs (AEDs). However, in some patients, seizures are resistant to AEDs despite appropriate treatment, and lifelong therapy is usually indicated (2).
Prolonged use of AEDs is associated with the increased risk of adverse events, such as drug interactions, cognitive dysfunction, idiosyncrasy, behavioral changes, and metabolic or endocrinal disturbances (2,3), particularly thyroid gland dysfunction.4 Thyroid hormones play an important role in the regulation of metabolism in many tissues. Therefore, disturbance of thyroid hormones has major implications for the growth and development of children (5).
The impact of AEDs on thyroid function is wellknown in adults. 6 However, disturbance of thyroid function in children receiving AEDs is a matter of controversy, and there is limited information in this context (4,7). Among drug therapies for epileptic children, most epileptologists preferred traditional AEDs, such as valproate, carbamazepine, and phenobarbital in the past. However, recently, major attention has been paid to newer drugs, such as levetiracetam, topiramate, oxcarbazepine, and lamotrigine. Newer AEDs are used as monotherapy, as well as add-on therapy for children with epilepsy (1). Previous studies have reported the effects of traditional AEDs on thyroid hormones in children.
However, there is limited evidence regarding the effects of newer AEDs (8).
Several studies reported no change in the level of thyroid hormones among children with epilepsy receiving AEDs (9,10), while others indicated significant alterations in the level of thyroid hormones (11,12). Administration of AEDs can result in subclinical hypothyroidism, which is defined as the elevation of thyroid stimulating hormone (TSH) level above the upper limit of the age-specific reference range, while the serum level of free thyroxine (FT4) is within its reference range. Subclinical hypothyroidism appears to be a benign condition with a low risk of conversion into overt hypothyroidism. This condition has no adverse effects on neuropsychological functions (13)(14)(15) .Changes in thyroid function can be attributed to the administration of AEDs, especially traditional AEDs. Therefore, in this study, we aimed to investigate the effects of traditional AEDs versus newer AEDs on the thyroid hormone profile of children with epilepsy. Declaration of Helsinki and its later amendments.

Materials & Methods
The exclusion criteria were as follows: 1) presence of an underlying etiology or drug-resistant seizures; 2) poor compliance; 3) polytherapy with more than one AED; 4) body mass index above the 95 th percentile for age and gender; 5) thyroxine replacement therapy and use of anti-thyroid drugs; 6) endocrinal, metabolic, or chronic medical disorders; and 7) symptoms suggestive of thyroid gland disorder.
Detailed history-taking, including demographic data, seizure type, epileptic syndrome, seizure etiology, onset age of epilepsy, selected AEDs, dosage of antiepileptic drugs, electroencephalographic (EEG) changes, and duration of AED therapy, was performed. Also, careful examination of thyroid glands for the presence of goiter was carried out.

Statistical analysis
Data and variables were analyzed using SPSS version 10.0 (Chicago, IL, USA). Values are expressed as mean±standard deviation (SD). Oneway analysis of variance (ANOVA), followed by post hoc Dunnett's test, was used to evaluate significant differences between the groups.
Qualitative data are also presented as number and percentage. To evaluate significant differences between the groups, Chi-square test was performed.
P-value less than 0.05 was considered statistically significant.

Results
Eighty epileptic children were enrolled in this study, including 48 males and 32 females. The participants' age ranged from three months to 15 years. Group  Table 2).

2(5)
(P =0.19)*.     (8,12). Subclinical hypothyroidism was detected in healthy control children with a prevalence of 0-7.7%. Generally, the association between epilepsy and altered thyroid function is not fully understood. Subclinical hypothyroidism has been reported in epileptic children before the onset of treatment; this may suggest that epilepsy plays a role in thyroid dysfunction (11,12).
Valproate, carbamazepine, and phenobarbital were the most commonly used traditional AEDs in our study. Previous studies showed a significant decrease in the serum level of FT4 and an increase in the serum level of TSH in patients treated with VPA; these changes were persistent throughout the study (8,11,28,29,30). In another study on adolescent girls with epilepsy, the group receiving valproate showed higher serum levels of TSH and lower serum levels of FT4, compared to  (41). Another mechanism might be related to interference in the hypothalamic-pituitarythyroid axis, responsible for the regulation of thyroid hormone production (10).
Carbamazepine can cause disturbance in thyroid hormones through inhibition of iodine uptake by the thyroid gland (42). We did not include a mechanistic approach in our study. However, based on our results, evaluation of thyroid hormone profile is recommended for epileptic children on long-term traditional AEDs, compared to newer drugs; therefore, complications due to thyroid dysfunction can be prevented.
The main limitation of this study is the small sample size. Therefore, larger prospective studies are needed on patients to support our findings.
In conclusion, Traditional AEDs have significant effects on the thyroid hormone profile of epileptic children on long-term therapy, compared to newer AEDs. Although these effects were not accompanied by clinical hypothyroidism, screening of thyroid hormone profile is recommended.
Further prospective studies are recommended on a larger sample of patients to confirm our results.